Modeling molecular diversity in cancer Integrating “omics”, mathematical models and functional cancer biology Lawrence Berkeley National Laboratory University of California, San Francisco University of California, Berkeley SRI International Netherlands Cancer Institute MD Anderson Cancer Center

Modeling molecular diversity in cancer A collection of cell lines as a model of molecular and biological diversity Three integrative biology examples  Associating pathways and markers with response  Modeling MEK signaling diversity using pathway logic  Bayesian network models of AKT signaling Identifying and understanding “omic” determinants of therapeutic response in breast cancer

Modeling molecular diversity in cancer A collection of cell lines as a model of molecular and biological diversity Three integrative biology examples  Associating markers with response  Modeling MEK signaling diversity using pathway logic  Bayesian network models of AKT signaling Identifying and understanding “omic” determinants of therapeutic response in breast cancer

Model requirements The molecular abnormalities that influence drug response in primary tumors must be functioning in the model The panel must have sufficient molecular diversity so that statistical analyses will have the power to identify molecular features associated with response Identifying and understanding “omic” determinants of therapeutic response

Luminal Basal Neve et al, Cancer Cell 2006 Chin et al, Cancer Cell, 2006 Frequency Genome location Expression Copy number Cell lines Tumors Cell lines as models of primary breast tumors A collection of 50 cell lines retain important transcriptional and genomic features of primary tumors Cell lines Tumors

Modeling molecular diversity in cancer A collection of cell lines as a model of molecular and biological diversity Three integrative biology examples  Associating markers with response  Modeling MEK signaling diversity using pathway logic  Bayesian network models of AKT signaling Integrating “omics”, mathematical models and functional cancer biology

Associating molecular markers with response to lapatinib Debo Das, 2007 TrainingTest Adaptive splines Prediction: Molecular markers and networks associated with sensitivity and resistance will predict clinical response

Test: Cell line markers predict response in HER2 positive patients EGF30001: A randomized, Phase III study of Paclitaxel + Lapatinib vs. Paclitaxel + Placebo HER2, GRB7, CRK, ACOT9, LJ31079, DDX5 GSK-LBNL collaboration

Modeling molecular diversity in cancer A collection of cell lines as a model of molecular and biological diversity Three integrative biology examples  Associating markers with response  Modeling MEK signaling diversity using pathway logic  Bayesian network models of AKT signaling Identifying and understanding “omic” determinants of therapeutic response in breast cancer

Protein abundances Transcript levels + Curated network model Hierarchical analysis of Pathway Logic states and rules Heiser, Spellman, Talcott, Knapp, Lauderote Baseline levels populate PL model states Rules define predicted pathway activity

Example network of one cell line

Hierarchical analysis of network features Prediction: PAK1 is required for network activation of MEK/ERK cascade in luminal cell lines

Test: PAK1 + luminal cell lines are more sensitive to MEK inhibitors CI1040GSK-MEKiU0126

Modeling molecular diversity in cancer A collection of cell lines as a model of molecular and biological diversity Three integrative biology examples  Associating pathways and markers with response  Modeling MEK signaling diversity using pathway logic  Bayesian network models of AKT signaling Identifying and understanding “omic” determinants of therapeutic response in breast cancer

Therapeutic agents show strong luminal subtype specificity Kuo, Guan, Hu, Bayani 2007 Sensitivity (-log10GI 50 ) Lapatinib Sensitivity (-log10GI 50 ) Paclitaxel

Subtype response metric log 10 la GI 50 - log 10 b GI 50 BasalLuminal AKT pathway inhibitors show strong luminal subtype specificity

Bayesian network analysis reveals AKT dependent signaling in luminal lines Mukherjee, Speed, Neve, et al., 2007 Prediction: PI3-kinase pathway mutations will occur preferentially in luminal subtype cell lines

Sensitivity (-log10GI 50 ) Test: AKT-inhibitor responsive cell lines carry PI3-kinase pathway mutations Kuo, Neve, Spellman et al., 2007 AKT pathway mutations 12/13 AKT pathway mutations in primary tumors are in the luminal subtype

Modeling molecular diversity in cancer A collection of cell lines as a model of molecular and biological diversity Three integrative biology examples  Associating pathways and markers with response  Modeling MEK signaling diversity using pathway logic  Bayesian network models of AKT signaling Integrating “omics”, mathematical models and functional cancer biology

Cell /Genome Biology Rich Neve Mina Bissell Philippe Gascard Frank McCormick Mary Helen Barcellos Hoff Rene Bernards Gordon Mills Comp. Biol Paul Spellman Laura Heiser Keith Lauderote Merrill Knapp Carolyn Talcott Sach Mukherjee Terry Speed Jane Fridlyand Bahram Parvin Lisa Williams Steve Ashton Surgery/Pathology Britt Marie Ljung Fred Waldman Shanaz Dairkee Laura Esserman Engineering Earl Correll Bob Nordmeyer Jian Jin Damir Sudar Exp. Therapeutics Maria Koehler Mike Press Michael Arbushites Tona Gilmer Barbara Weber Richard Wooster ICBP, SPORE, GSK, Affymetrix, Genentech, Panomics, Cellgate, Cell Biosciences, Komen, Avon, EGF30001 Trial Investigators Collaborating Laboratories & Support